The formation of salts is one of the possibilities of stabilizing medicinal substances. Salts can be prepared during the manufacture of the dosage form, saving time, reducing cost and environmental impact. Several studies have documented significant enalapril maleate (EM) instability. EM decomposes into diketopiperazine (DKP) and diacid (DA) impurities at elevated temperature and humidity. Notably, toxic DKP is preferentially formed at pH 2 - 3, and DA formation dominates at pH values above 5. This instability raises concerns about the therapeutic efficacy and safety of the drug. The proposed stabilization strategy involves the "in situ" conversion of EM into a stable sodium salt. This is achieved by incorporating suitable ionic excipients, specifically alkali metal salts and an ethanol-based hydrolysis inhibitor, into the granulation solution. This method effectively inhibits the deethylation to DA and provides uniform tablets with minimal DKP content to ensure long-term five-year stability. In general, these tablets show a lower content of degradation products compared to the stability results reported so far in various generics, and the amount of impurities meets the ICH Q3B (R2) requirements.

• Klíčová slova
• Alkaline excipients, Diacid, Diketopiperazine, Enalapril maleate, Neutralization, Sodium salt, Stability, Tablets,
• MeSH
• enalapril * chemie   MeSH
• farmaceutická chemie metody   MeSH
• hydrolýza MeSH
• ionty chemie   MeSH
• koncentrace vodíkových iontů MeSH
• pomocné látky * chemie   MeSH
• příprava léků metody   MeSH
• soli chemie   MeSH
• stabilita léku MeSH
• tablety chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• enalapril * MeSH
• ionty MeSH
• pomocné látky * MeSH
• soli MeSH
• tablety MeSH

In order to broaden the applicability of the molecular dynamics technique and to further validate the efficacy of a computational protocol recently developed in our laboratory, the present study aims to elucidate the enantiorecognition mechanisms involving four zwitterionic Cinchona alkaloid-based CSPs under reversed-phase (RP) conditions. In this study, we use the enantiomeric dipeptides D-leucine-D-phenylalanine and L-leucine-L-phenylalanine as probes to investigate the properties of CHIRALPAK ZWIX(+) and ZWIX(-), as well as ZWIX(+A) and ZWIX (-A). The Leu-Phe dipeptide has considerable potential in the pharmaceutical field due to its potential applications in drug delivery, therapeutics and as a building block for peptidomimetics. Furthermore, Leu-Phe is one of the few uncapped dipeptides composed of natural amino acids capable of forming stable hydrogels. The in silico protocol was successfully optimized by setting the simulation box size, run time, and number of frames to record to generate molecular dynamics trajectories as informative as possible. Importantly, the analyses were in complete agreement with the experimental EO, providing insights into the driving forces involved in the enantiorecognition mechanism. In particular, salt bridges and hydrogen bonds were confirmed as the primary interactions, while π-π and π-cation interactions were identified as complementary to facilitate the SO-SA association.

• Klíčová slova
• HPLC, enantiorecognition mechanism, molecular dynamic simulations, zwitterionic Cinchona alkaloids‐based chiral stationary phases,
• MeSH
• dipeptidy * chemie   MeSH
• fenylalanin * chemie   MeSH
• simulace molekulární dynamiky * MeSH
• stereoizomerie MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dipeptidy * MeSH
• fenylalanin * MeSH

High-salt diets (HSDs) are known to impact blood pressure and cardiovascular health, but their effects on glucose metabolism, liver function, and gut microbiota remain poorly understood. This study investigates how long-term HSD affects these physiological processes and evaluates the potential therapeutic effects of ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). Male Sprague-Dawley rats were fed a normal salt diet (0.3% NaCl), a moderate salt diet (2% NaCl), or a high-salt diet (8% NaCl) for 12 wk. Two subgroups in the HSD condition received telmisartan or enalapril. We assessed blood pressure, glucose homeostasis, liver inflammation, pancreatic function, and gut microbiota composition. HSD rats exhibited significantly higher blood pressure [130 ± 2 mmHg in normal diet (ND) vs. 144 ± 4 mmHg in HSD; P < 0.01], reduced fasting insulin (1.33 ± 0.14 ng/mL in ND vs. 0.60 ± 0.05 ng/mL in HSD; P < 0.01), and gut microbiota dysbiosis, with a 71% reduction in Ruminococcus species (P = 0.018). Liver inflammation, indicated by an increase in CD68+ macrophages, was also observed in the HSD group. Telmisartan treatment significantly reduced liver inflammation but did not fully restore metabolic homeostasis. HSD disrupts multiple physiological systems, including glucose metabolism and liver function, partly through gut microbiota alterations. ACEIs and ARBs provided partial protection, highlighting the need for multitargeted interventions to mitigate high-salt diet effects.NEW & NOTEWORTHY High-salt diet induces multisystem disruptions, including liver inflammation, reduced insulin levels, and gut microbiota imbalance. ACEIs and ARBs showed limited efficacy, highlighting the need for comprehensive therapeutic approaches.

• Klíčová slova
• ACE inhibitor, angiotensin II receptor blocker, high-salt diet, rat physiology,
• MeSH
• antagonisté receptorů pro angiotenzin * farmakologie   MeSH
• enalapril farmakologie   MeSH
• glukosa * metabolismus   MeSH
• inhibitory ACE * farmakologie   MeSH
• játra * účinky léků   metabolismus   MeSH
• krevní glukóza metabolismus   účinky léků   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• kuchyňská sůl * škodlivé účinky   MeSH
• potkani Sprague-Dawley MeSH
• střevní mikroflóra * účinky léků   MeSH
• telmisartan farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antagonisté receptorů pro angiotenzin * MeSH
• enalapril MeSH
• glukosa * MeSH
• inhibitory ACE * MeSH
• krevní glukóza MeSH
• kuchyňská sůl * MeSH
• telmisartan MeSH

Phosphorylated peptides are instrumental in studying protein phosphorylation events. In the present study, Raman optical activity (ROA) is employed to elucidate the structure of a dipeptide, L-alanyl-L-glutamine (L-Ala-L-Gln) and its two differently alkylated N-phosphorylated derivatives. Theoretical simulations were conducted to aid the interpretation of peptide conformation variations upon phosphorylation, and of the measured Raman and ROA spectra. Induced circularly polarized luminescence (CPL) was also recorded in solution, in the presence of a simple europium aqua ion. As the spectra are peptide specific, this type of stereochemical analysis is expected to aid identification of the phosphorylation sites also in other peptides and possibly proteins.

• Klíčová slova
• Biomolecular spectroscopy, Circularly polarized luminescence, Molecular dynamics, Peptide phosphorylation, Raman optical activity,
• MeSH
• dipeptidy * chemie   MeSH
• fosforylace MeSH
• molekulární modely MeSH
• Ramanova spektroskopie * metody   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alanylglutamine MeSH Prohlížeč
• dipeptidy * MeSH

BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibitor (ARPI) and taxane therapy. We aimed to investigate the efficacy of 177Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer. METHODS: In this phase 3, randomised, controlled trial conducted at 74 sites across Europe and North America, taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI were randomly allocated (1:1) to open-label, intravenous 177Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). Crossover from ARPI change to 177Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is registered with ClinicalTrials.gov (NCT04689828) and is ongoing. In this primary report of the study, we present primary (first data cutoff) and updated (third data cutoff) analyses of radiographic progression-free survival; all other data are based on the third data cutoff. FINDINGS: Overall, of the 585 patients screened, 468 met all eligibility criteria and were randomly allocated between June 15, 2021 and Oct 7, 2022 to receive 177Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of 177Lu-PSMA-617 cycles was 6·0 (IQR 4·0-6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive 177Lu-PSMA-617. In the primary analysis (median time from randomisation to first data cutoff 7·26 months [IQR 3·38-10·55]), the median radiographic progression-free survival was 9·30 months (95% CI 6·77-not estimable) in the 177Lu-PSMA-617 group versus 5·55 months (4·04-5·95) in the ARPI change group (hazard ratio [HR] 0·41 [95% CI 0·29-0·56]; p<0·0001). In the updated analysis at time of the third data cutoff (median time from randomisation to third data cutoff 24·11 months [IQR 20·24-27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30-14·19) in the 177Lu-PSMA-617 group versus 5·59 months (4·21-5·95) in the ARPI change group (HR 0·49 [95% CI 0·39-0·61]). The incidence of grade 3-5 adverse events was lower in the 177Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade 5 [none treatment related]) than the ARPI change group (112 [48%] of 232; five [2%] grade 5 [one treatment related]). INTERPRETATION: 177Lu-PSMA-617 prolonged radiographic progression-free survival relative to ARPI change, with a favourable safety profile. For patients with PSMA-positive metastatic castration-resistant prostate cancer who are being considered for a change of ARPI after progression on a previous ARPI, 177Lu-PSMA-617 may be an effective treatment alternative. FUNDING: Novartis.

• MeSH
• androsteny * terapeutické užití   MeSH
• antagonisté androgenních receptorů terapeutické užití   MeSH
• benzamidy terapeutické užití   MeSH
• dipeptidy * terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• fenylthiohydantoin * terapeutické užití   MeSH
• heterocyklické sloučeniny monocyklické * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lutecium * terapeutické užití   MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   patologie   MeSH
• nitrily * terapeutické užití   MeSH
• prostatický specifický antigen krev   MeSH
• radionuklidy terapeutické užití   MeSH
• senioři MeSH
• taxoidy terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• abiraterone MeSH Prohlížeč
• androsteny * MeSH
• antagonisté androgenních receptorů MeSH
• benzamidy MeSH
• dipeptidy * MeSH
• enzalutamide MeSH Prohlížeč
• fenylthiohydantoin * MeSH
• heterocyklické sloučeniny monocyklické * MeSH
• lutecium * MeSH
• nitrily * MeSH
• Pluvicto MeSH Prohlížeč
• prostatický specifický antigen MeSH
• radionuklidy MeSH
• taxoidy MeSH

Thank you very much for your comment [...].

• MeSH
• beta-alanin * aplikace a dávkování   MeSH
• karnosin * MeSH
• lidé MeSH
• potravní doplňky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• beta-alanin * MeSH
• karnosin * MeSH

Chromatographic behavior of novel chiral stationary phases with bonded selectors based on Cinchona alkaloids modified with dipeptides was studied using dipeptides as probe molecules. Buffer-free and salt containing hydro-organic solutions were used as the mobile phases. The selectors exhibit pseudoenantiomeric behavior with respect to the L/D or LL/DD enantiomers and do not behave so with respect to the LD/DL enantiomers. The alkaloid part of the selectors is the driver of enantioselectivity, while the dipeptide substituent plays a modulating role. The quinidine-based selectors demonstrate stronger adsorption affinity and higher enantioselectivity as compared to the quinine-based selectors. The dipeptide analytes containing a glycyl fragment are weaker retained and their enantiomers are worse separated comparing to dipeptides with both units being larger amino acids. Moreover, a phenyl group in the structure of a dipeptide analyte facilitates enantioseparation. The effect of the mobile phase composition on retention depends on the hydrophobicity of an analyte. Hydrophobic dipeptides are better eluted by methanol-rich solvents, hydrophilic dipeptides are better eluted with water-rich solvents, and dipeptides with an intermediate hydrophobicity demonstrate a U-shaped or more complicated dependence of the retention factor on the percentage of methanol. Even a small buffer addition to the mobile phase decreases retention, but the ion-exchange mechanism was not confirmed. The effect of an electrolyte is rather due to the shielding of the charged groups of the selector reducing thereby electrostatic interaction between the selector and analyte. Efficiency of the novel columns is comparable to that of other brush-type chiral columns, the highest achieved number of the theoretical plates per 1 m varying between 30,000 and 40,000.

• Klíčová slova
• Chiral separation, Chiral zwitterion ion exchangers, Cinchona alkaloids, Dipeptides, Zwitterionic species,
• MeSH
• chinin chemie   izolace a purifikace   MeSH
• chininové alkaloidy * chemie   MeSH
• chromatografie s reverzní fází * metody   MeSH
• dipeptidy * chemie   izolace a purifikace   MeSH
• hydrofobní a hydrofilní interakce * MeSH
• stereoizomerie MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Publikační typ
• časopisecké články MeSH

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.

• MeSH
• akutní poškození ledvin * chemicky indukované   patologie   metabolismus   prevence a kontrola   farmakoterapie   MeSH
• cisplatina * toxicita   MeSH
• diminazen * analogy a deriváty   farmakologie   terapeutické užití   MeSH
• inhibitory ACE farmakologie   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   patologie   metabolismus   MeSH
• lisinopril * farmakologie   MeSH
• potkani Wistar * MeSH
• protinádorové látky toxicita   MeSH
• valsartan * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• cisplatina * MeSH
• diminazen * MeSH
• inhibitory ACE MeSH
• lisinopril * MeSH
• protinádorové látky MeSH
• valsartan * MeSH

Glutamate carboxypeptidase II (GCPII, also known as PSMA or FOLH1) is responsible for the cleavage of N-acetyl-aspartyl-glutamate (NAAG) to N-acetyl-aspartate and glutamate in the central nervous system and facilitates the intestinal absorption of folate by processing dietary folyl-poly-γ-glutamate in the small intestine. The physiological function of GCPII in other organs like kidneys is still not known. GCPII inhibitors are neuroprotective in various conditions (e.g., ischemic brain injury) in vivo; however, their utilization as potential drug candidates has not been investigated in regard to not yet known GCPII activities. To explore the GCPII role and possible side effects of GCPII inhibitors, we performed parallel metabolomic and lipidomic analysis of the cerebrospinal fluid (CSF), urine, plasma, and brain tissue of mice with varying degrees of GCPII deficiency (fully deficient in Folh1, -/-; one allele deficient in Folh1, +/-; and wild type, +/+). Multivariate analysis of metabolites showed no significant differences between wild-type and GCPII-deficient mice (except for NAAG), although changes were observed between the sex and age. NAAG levels were statistically significantly increased in the CSF, urine, and plasma of GCPII-deficient mice. However, no difference in NAAG concentrations was found in the whole brain lysate likely because GCPII, as an extracellular enzyme, can affect only extracellular and not intracellular NAAG concentrations. Regarding the lipidome, the most pronounced genotype-linked changes were found in the brain tissue. In brains of GCPII-deficient mice, we observed statistically significant enrichment in phosphatidylcholine-based lipids and reduction of sphingolipids and phosphatidylethanolamine plasmalogens. We hypothesize that the alteration of the NAA-NAAG axis by absent GCPII activity affected myelin composition. In summary, the absence of GCPII and thus similarly its inhibition do not have detrimental effects on metabolism, with just minor changes in the brain lipidome.

• Klíčová slova
• FOLH1, N-acetyl-aspartyl-glutamate, folyl-poly-γ-glutamyl hydrolase I, glutamate carboxypeptidase II, lipidomics, metabolomics,
• MeSH
• dipeptidy metabolismus   MeSH
• glutamátkarboxypeptidasa II * genetika   metabolismus   MeSH
• kyselina glutamová MeSH
• lipidomika * MeSH
• lipidy chemie   MeSH
• metabolomika * MeSH
• mozek metabolismus   MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dipeptidy MeSH
• Folh1 protein, mouse MeSH Prohlížeč
• glutamátkarboxypeptidasa II * MeSH
• isospaglumic acid MeSH Prohlížeč
• kyselina glutamová MeSH
• lipidy MeSH

Chiral resolution of polar organic compounds such as amino acids and peptides represents an important chromatographic task due to increasing significance of natural species, which play important signaling and regulatory roles in the living organisms. Despite the number of available chiral stationary phases, this task remains challenging, since not many of the commercially available systems are capable to resolve non-derivatized zwitterionic species. In this study, we present a target-oriented design of a new class of chiral selectors. Pursuing the goal to separate amino acids, and especially short peptides, we have combined Cinchona alkaloids - quinine and quinidine - with three different biogenic dipeptides. We have synthesized six different chiral stationary phases, with selector loading of ∼200 μmol g-1, and tested their chiral recognition capabilities for acidic, basic and zwitterionic analytes using various mobile phases. We have observed that all chiral stationary phases retain the chiral anion exchange capability known for commercially available Cinchona-based columns leading to baseline or partial resolution of six out of ten analytes. The performance in chiral resolution of basic analytes is not optimum due to the weak cation exchange character of the peptidic residue. However, we report on encouraging results in the chiral resolution of short peptides, for which, depending on their structure, we see the chiral resolution of up to three stereoisomers (from four possible) in a preliminary screening.

• Klíčová slova
• Chiral separation, Chiral zwitterion ion exchangers, Cinchona alkaloids, Dipeptides, N-protected amino acids,
• MeSH
• aminokyseliny chemie   MeSH
• aminy MeSH
• chinidin MeSH
• chinin chemie   MeSH
• chininové alkaloidy * chemie   MeSH
• chinovník * MeSH
• dipeptidy MeSH
• stereoizomerie MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminokyseliny MeSH
• aminy MeSH
• chinidin MeSH
• chinin MeSH
• chininové alkaloidy * MeSH
• dipeptidy MeSH